Selective synthesis of novel quinolones-amino esters as potential antibacterial and antifungal agents: Experimental, mechanistic study, docking and molecular dynamic simulations

Moussaoui, Oussama; Byadi, Said; Hachim, Mouhi Eddine; Sghyar, Riham; Bahsis, Lahoucine; Moslova, Karina; Aboulmouhajir, Aziz; Rodi, Youssef Kandri; Podlipnik, Črtomir; Hadrami, El Mestafa El; Chakroune, S.

doi:10.1016/j.molstruc.2021.130652

Cited by 19 publications

(16 citation statements)

References 73 publications

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“…In the same context, its docking with the crystal structure of Mcl-1 in the Maestro package implemented in Schrodinger software gave rise to a good docking score. [36,37] As expected, Table 8 exhibits its high activity according to these models, confirming that the proposed ligand is found very active and can be a Taking into account the inhibitory activity predicted values of the proposed compound as well as its docking score, which are very encouraging, it deserves to be tested in-vitro for more evaluating its activity against Mcl-1 protein. For further analysis to confirm the favorable interaction between the designed inhibitors and the binding site of the Mcl-1 protein, we evaluated the 2D and 3D interactions of the complex formed by them.…”

Section: Design and Evaluate The Interaction Of The Designed Compound...supporting

confidence: 76%

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Discovery of a New Mcl‐1 Protein Inhibitor through the QSAR Approach and Molecular Docking Study

Byadi

Sadik

Hachim

et al. 2022

Advcd Theory and Sims

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In this study, a quantitative structure‐activity relationship (QSAR) model of anticancer activity against myeloid cell leukemia 1 (Mcl‐1) for a series of 41 tricyclic indole diazepinone derivatives is established. Three different modeling methods, multiple linear regression (MLR), partial least square (PLS), and artificial neural network (ANN) are investigated to perform a QSAR model with significant predictiveness. A clustering method is also used for dividing all compounds into training and external test (ET) sets. Component principal analysis is used to eliminate the redundancy between descriptors. The accuracy and predictability of the proposed models are proven by comparing their key statistical terms. The good results obtained with the internal and external validations (EV) show that the proposed models can predict high‐performance activities and that the selected descriptors are pertinent. This model is also validated using internal validation (IV), mainly using cross‐validation (leave‐many‐out (LMOCV)). The applicability domain (AD) is identified. Based on the SAR map analysis, a novel Mcl‐1 inhibitor with a good predicted activity using the best model is proposed, the interaction of the designed compound with the binding site of Mcl‐1 protein is evaluated and its docking score is found high.

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Section: Design and Evaluate The Interaction Of The Designed Compound...supporting

confidence: 76%

“…In the same context, its docking with the crystal structure of Mcl‐1 in the Maestro package implemented in Schrodinger software gave rise to a good docking score. [ 36,37 ]…”

Section: Resultsmentioning

confidence: 99%

Discovery of a New Mcl‐1 Protein Inhibitor through the QSAR Approach and Molecular Docking Study

Byadi

Sadik

Hachim

et al. 2022

Advcd Theory and Sims

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“…The reaction of the 2‐quinolone derivatives with propargyl bromide under phase transfer catalysis (PTC)[ 52 , 53 , 54 , 55 ] conditions (liquid‐solid) in dimethylformamide in the presence of potassium carbonate and tetra‐n‐butylammonium bromide (TBAB) led to 1‐propargyl‐2‐quinolone ( 2 a , 2 b ) with good yields. The synthesis of the target compounds 2 a and 2 b was achieved by first preparing the quinolone‐carboxamides 1 a and 1 b using the coupling reaction between 2‐quinolone carboxylic acids ( a , b ) and L‐alanine‐OMe in the presence of HBTU as an activating agent and triethylamine (TEA) and chloroform (CHCl 3 ) as solvents for 12 hours at room temperature.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, in vitro and in silico Characterization of 2‐Quinolone‐L‐alaninate‐1,2,3‐triazoles as Antimicrobial Agents

et al. 2022

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Due to the ever‐increasing antimicrobial resistance there is an urgent need to continuously design and develop novel antimicrobial agents. Inspired by the broad antibacterial activities of various heterocyclic compounds such as 2‐quinolone derivatives, we designed and synthesized new methyl‐(2‐oxo‐1,2‐dihydroquinolin‐4‐yl)‐L‐alaninate‐1,2,3‐triazole derivatives via 1,3‐dipolar cycloaddition reaction of 1‐propargyl‐2‐quinolone‐L‐alaninate with appropriate azide groups. The synthesized compounds were obtained in good yield ranging from 75 to 80 %. The chemical structures of these novel hybrid molecules were determined by spectroscopic methods and the antimicrobial activity of the compounds was investigated against both bacterial and fungal strains. The tested compounds showed significant antimicrobial activity and weak to moderate antifungal activity. Despite the evident similarity of the quinolone moiety of our compounds with fluoroquinolones, our compounds do not function by inhibiting DNA gyrase. Computational characterization of the compounds shows that they have attractive physicochemical and pharmacokinetic properties and could serve as templates for developing potential antimicrobial agents for clinical use.

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“…This result is similar to those described in the literature for compounds containing the same substituents. 60 On the other hand, the Gram-negative bacteria E. coli is inhibited by almost the majority of the tested hybrid compounds with moderate to good antibacterial effect in comparison with the control. Among the evaluated hybrid compounds, compound 6g (Ar = p-OCH 3 (C 6 H 4 ), Ar 1 = p-NO 2 (C 6 H 4 )) is the most active against E. coli with an inhibition zone of (15 ± 01) mm and an inhibition rate of 62.5% compared to streptomycin (24 ± 1.5 mm).…”

Section: Mechanistic Studymentioning

confidence: 97%

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

et al. 2022

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A series of new heterocycle hybrids incorporating pyrazole and isoxazoline rings was successfully synthesized, characterized, and evaluated for their antimicrobial responses. The synthesized compounds were obtained utilizing N-alkylation and 1,3-dipolar cycloaddition reactions, as well as their structures were established through spectroscopic methods and confirmed by mass spectrometry. To get more light on the regioselective synthesis of new hybrid compounds, mechanistic studies were performed using DFT calculations with B3LYP/6-31G(d,p) basis set. Additionally, the results of the preliminary screening indicate that some of the examined hybrids showed potent antimicrobial activity, compared to standard drugs. The results confirm that the antimicrobial activity is strongly dependent on the nature of the substituents linked pyrazole and isoxazoline rings. Furthermore, molecular docking studies were conducted to highlight the interaction modes between the investigated hybrid compounds and the Escherichia coli and Candida albicans receptors. Notably, the results demonstrate that the investigated compounds have strong protein binding affinities. The stability of the formed complexes by the binding between the hybrid compound 6c, and the target proteins was also confirmed using a 100 ns molecular dynamics simulation. Finally, the prediction of ADMET properties suggests that almost all hybrid compounds possess good pharmacokinetic profiles and no signs of observed toxicity, except for compounds 6e, 6f, and 6g.

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Selective synthesis of novel quinolones-amino esters as potential antibacterial and antifungal agents: Experimental, mechanistic study, docking and molecular dynamic simulations

Cited by 19 publications

References 73 publications

Discovery of a New Mcl‐1 Protein Inhibitor through the QSAR Approach and Molecular Docking Study

Discovery of a New Mcl‐1 Protein Inhibitor through the QSAR Approach and Molecular Docking Study

Design, Synthesis, in vitro and in silico Characterization of 2‐Quinolone‐L‐alaninate‐1,2,3‐triazoles as Antimicrobial Agents

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

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